Chemical process

ABSTRACT

1. A METHOD FOR REDUCING THE CHOLESTEROL AND LIPID LEVELS OF MAMMALS WHICH COMPRISES; A. ADMINISTERING TO A MAMMAL IN HYPERCHOLESTEREMIC OR HYPERLIPIDEMIC CONDITION; B. A DAILY DOSAGE OF FROM 25 TO 2500 MG. OF A COMPOUND OF THE FORMULA:   3,7-DI(X),3,7-DI(Y),17-(R-CO-CH2-CH2-CH(-CH3)-)-   ANDROST-11-ENE   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF GLYCINE, TAURINE, HYDROXY, ACYLOXY AND ALKOXY; EACH X IS HYDROGEN; EACH Y IS SELECTED FROM THE GROUP CONSISTING OF HYDROXY, ACYLOXY, AND ALKOXY; WHEN TAKEN TOGETHER X AND Y IS OXO (O=); WHEREIN EACH ACYLOXY RADICAL IS FROM A HYDROCARBON CARBOXYLIC ACID OF LESS THAN 12 CARBON ATOMS; AND THE NON-TOXIC, PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF.

United States Patent 3,839,565 CHEMICAL PROCESS William H. Saltzman, New Rochelle, N.Y., assignor to Intellectual Property Development Corporation, New Rochelle, N.Y.

No Drawing. Filed Oct. 31, 1972, Ser. No. 302,508 Int. Cl. C07c 169/40 US. Cl. 424-238 12 Claims ABSTRACT OF THE DISCLOSURE A method of reducing the levels of cholesterol and other lipids in mammals, which comprises administering to said mammals an effective amount of a substance having the formula:

wherein R is selected from the group consisting of an amino acid, for example glycine or turine, hydroxy, acyloxy or alkoxy; and each X is hydrogen; and each Y is hydroxy, acyloxy or alkoxy; and when taken together, X and Y is oxo (0:); and the non-toxic, pharmaceutically acceptable salts thereof.

SPECIFICATION l l I I I wherein R is an amino acid, for example,

NHCH CH SO H or NHCH SO H,

hydroxy, acyloxy or alkoxy; each X is hydrogen; Y is hydroxy, acyloxy, or alkoxy; and when taken together, X and Y is 0x0 (0:); and the non-toxic, pharmaceutically acceptable salts thereof. By the practice of this invention, it has been found that it is possible to safely and effectively lower the cholesterol and other lipid levels of the mammals being treated here under. More specifically, it has been found that the administration of effective amounts of the compounds of Formula I above, to mammals in a hyperlipidemic or hypercholesteremic state or condition results in a significant reduction in the cholesterol or lipid levels of the treated mammal. Among those hypercholesteremic and hyperlipidemic states or 3,839,565 Patented Oct. 1, 1974 conditions in which the compositions of this invention have been found to be effective may be included such conditions as hypercholesterolemia, hypertriglyceridemia and cholelithiasis, among others. It has been found that most satisfactory results are obtained when a patient suffering from cholelithiasis, i.e. cholesterol gallstones, is treated with the compositions of this invention. In these cases, it has been discovered that after relatively short periods of treatment with the compositions of this invention, the patients gallstones begin to rapidly dissolve, without the need for surgery.

The preferred compounds of this invention are those of Formula L wherein Y and R are hydroxy, although the other compounds also provide satisfactory results. Among the specific compounds which may be employed in the practice of this invention may be included such compounds as, 3a,7a dihydroxy 5fi-chol-l1-en-24-oic acid, 3a,7a-diacyloxy-5/3-chol-l1-en-24-oic acid, for example, 30:,70: diacetoxy-SB-chol-l1-en-24-oic acid, 3,7-dioxy-5B- chol-11-en-24-oic acid, 3oz acyloxy-7a-hydroxy-5fi-chol- 11-en-24-oic acid, and other like compounds.

The non-toxic, pharmaceutically acceptable salts which may be employed in the practice of this invention include such salts as the alkali metal salts of the compounds of Formula I, for example, the sodium and potassium salts, and other like salts well known to the art.

The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids, the lower alkenoic acids, the monocyclic aryl carboxylic acids, the monocyclic aryl lower alkanoic acids, the cycloalkane carboxylic acids and the cycloalkene carboxylic acids. The preferred alkoxy radicals are those of less than twelve carbon atoms and may be straight or branch chain, and may include such moieties as, methoxy, ethoxy, propoxy, t.-butoxy, pentoxy and the like.

In the practice of this invention satisfactory results are obtained when the compositions of this invention are administered to the mammal being treated in a daily amount of from about 25 to about 2.500 milligrams per day. The most preferred route of administration of the compositions of this invention is perorally, although other routes of administration may also provide satisfactory results. Optimal results may be obtained in the practice of this invention when the compositions of this invention are orally administered to the patient being treated at a daily dosage level of from about 50 to 1500 milligrams, over an extended period sufficient to provide to beneficial results desired.

To achieve the purposes and objectives of this invention, the active substances of Formula 1 hereof, may be incorporated into such suitable final dosage forms as may be satisfactorily prepared and employed by the worker skilled in the art. Thus, the commonly employed pharmaceutically acceptable dosage forms suitable for administration and preferably oral administration, containing the active substances of Formula I in suflicient concentration to attain the desired results may be utilized. The pharmaceutically acceptable, non-toxic, inert carriers usually employed for such purposes may be utilized to prepare such dosage forms as, tablets, capsules, elixirs, solutions, suspensions, and the like. Most preferably, satisfactory results are obtained by the use of tablets or capsules containing the active substance in a concentration of from 50 to 500 milligrams each, although other concentrations may also be utilized satisfactorily.

The invention may be further illustrated by the following examples:

EXAMPLE 1 Final orally administerable dosage forms incorporating the active substances set forth in Table A below, were prepared and administered on a daily basis to patients in a'hypercholesteremic or hyperlipidemic condition. These compositions were administered to the patients over an extended period of time during which the patients experienced a significant reduction in their cholesterol or lipid levels, without untoward side effects.

TABLE A Compound: Daily Dosage, Mg. 3a,7u-dihydroxy-5,6-chol-l1-en-24-oic acid 500 3a,7a-dihydroxy-5j8-chol-11-en-24-oic acid 7-50 3a,7a-diaoetoxy-5,8-chol-l1-en-24-oic acid 1000 EXAMPLE 2 Patients suffering from cholelithiasis, i.e. cholesterol gallstones, were treated with the compounds set forth in Table B below, by oral administration thereof over an extended period of time. In each case, the patient being treated experienced a significant reduction in the size of their gallstones.

TABLE B Compound: Daily Dosage, Mg. 3a,7a,dihydroxy-5;8-chol-11-en-24-oic acid 750 The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is: 1. A method for reducing the cholesterol and lipid levels of mammals which comprises:

a. Administering to a mammal in hypercholesteremic or hyperlipidemic condition; b. A daily dosage of from 25 to 2500 mg. of a compound of the formula:

wherein R is selected from the group consisting of glycine, taurine, hydroxy, acyloxy and alkoxy; each X is hydrogen; each Y is selected from the group consisting of hydroxy, acyloxy, and alkoxy; when taken together X and Y is oxo wherein each acyloxy radical is from a hydrocarbon carboxylic acid of less than 12 carbon atoms; and the non-toxic, pharmaceutically acceptable salts thereof.

2. The method of Claim 1 wherein each X is hydrogen; and each Y is hydroxy.

3. The method of Claim 1 wherein R is selected from the group consisting of glycine, taurine, hydroxy and acetoxy.

4. The method of Claim 1 wherein R is hydroxy; each X is hydrogen; and each Y is selected from the group consisting of hydroxy, acyloxy and alkoxy, wherein the acyloxy radical is from a hydrocarbon carboxylic acid of less than 12 carbon atoms.

5. The method of Claim 1 wherein the compound is selected from the group consisting of 3a,70c-dihydIOXy- 5fl-cho1-1l-en-24-oic acid; 3a,7a-diacetoxy-5 3-chol-ll-en- 24-oic acid; and 3,7-dioxy-5p-chol-11-en-24-oic acid.

6. The method of Claim 1 wherein the compound is 3a,7a,dihydroxy-5}8-chol-11-en-24-oic acid.

7. A pharmaceutical composition useful in the treatment of hypercholesteremia or hyperlipidemia which comprises:

a. As an active ingredient, a compound of the formula:

wherein R, X and Y are as defined in Claim 1; or a non-toxic, pharmaceutically acceptable salt thereof; and

b. a non-toxic, pharmaceutically acceptable carrier,

suitable for oral administration of the said composition.

8. A pharmaceutical composition useful in the treatment of hypercholesteremia or hyperlipidemia, which comprises:

a. As an active ingredient, a compound of the formula:

wherein R is selected from the group consisting of glycine, taurine, hydroxy and acyloxy; each X is hydrogen; each Y is selected from the group consisting of hydroxy, acyloxy and alkoxy; X and Y when taken together is 0x0 (0:); wherein each acyloxy radical is from a hydrocarbon carboxylic acid of less than 12 carbon atoms; or the non-toxic, pharmaceutically acceptable salt thereof; and b. a non-toxic, pharmaceutically acceptable carrier, suitable for oral administration of said composition. 9. The pharmaceutical composition of Claim 7, wherein R is hydroxy.

10. The pharmaceutical composition of Claim 7, wherein each Y is hydroxy.

11. The pharmaceutical composition of Claim 7, wherein X is hydrogen; R is hydroxy; and each Y is hydroxy.

12. The composition of Claim 7, wherein the compound is selected from the group consisting of 3a,7a-dihydroxy-Sfl-chol-l1-en-24-oic acid; 3a,7u-diacetoxy-5flchodl-11-en-24-oic acid; and 3,7-dioxy-5fl-chol-11-en-24-oic acr References Cited ELBERT L. ROBERTS, Primary Examiner '1 US. Cl. X.R. 260397.l, 397.2

UNITED STATES PATEN OFFICE CERTIFICATE OF CORRECTION Patent No. 5,859 565 I Dated 97A Inventor(s) Wi lliam H. Saltzman It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

The, following Claims should be added:

I V v "13. The l, wherein in Step a; the hyperchblester'emicit rel hy b erlipi demie 'cdn diti-on is selected from the grqup consist i r j g'b'f' hy'p erc holest'eriol e'mja, nypertri I glyceridemia arlld ch o lefl-iit h i a si s I I I 14 The pharmaceut ic al eblnposi ti on ef Cleim 7,

he e n the eorhpound its 34 ,7d -dihydrox y-5p -cho1 -1 1 -en -24-0i c acid." I Signed and sealed this 7th day of January-U275.

(SEAL) Attest mccoY M. GIBS ON JR. c. MARSHALL mm:

Attesting Officer Commissioner of Patents USCOMM-DC 60370-P69 FORM PO-1050 (10-69) r u.s, eovie uueuv rnnmns omen; 93 o 

1. A METHOD FOR REDUCING THE CHOLESTEROL AND LIPID LEVELS OF MAMMALS WHICH COMPRISES; A. ADMINISTERING TO A MAMMAL IN HYPERCHOLESTEREMIC OR HYPERLIPIDEMIC CONDITION; B. A DAILY DOSAGE OF FROM 25 TO 2500 MG. OF A COMPOUND OF THE FORMULA: 